2-formyl-delta2-androstenes



3,077,485 Z-FOIhViYL-A -ANDRUSTENES Albert Bowers, John Edwards, andJames C. flrr, all of Mexico City, Mexico, assiguors, by mesneassignments, to Syntax Corporation, a corporation of Panama N Drawing.Fiied Aug. 3, i961, ger. No. 128374- Claims priority, appiication MexicoJan. 19, 1961 tllaims. (ill. 269-37.4)

The present invention relates to certain new cyclopentanophenanthrencderivatives and to a method for the preparation thereof.

More particularly, it reiates to a method for preparing 2-formyl-A-l7B-hydroxy-androstenes, which may further possess a 17a-8lkY1,allcenyl or alkinyi group, as well as their esters and the correspondingl9-nor-compounds.

Such compounds are hormones of the androgenic type, which show afavorable anabolic-androgenic ratio; they further possessanti-estrogenic activity, lower the blood cholesterol level and are goodstimulants of the appetite.

The novel compounds which are obtained by the method object of thepresent invention are represented by the following formula:

In the above formula R represents hydrogen or methyl; R representshydrogen, a lower ailryl group of 1 to 5 carbon atoms such as methyl,ethyl and propyi, or a lower alkenyl or alldnyl group such as vinyl,ethynyi or propynyl; R represents hydrogen or an acyl group derived froma carboxylic acid of less than 12 carbon atoms, saturated orunsaturated, of straight, branched, cyclic or mixed cyclic-aliphaticchain, substituted or not with methoxy, halogen or other groups; typicalsuch esters are the acetate, propionate, butyrate, vaierate,hemi-succinate, enanthate, caproate, benzoate, undecenoate,trimethylacetate, phenoxyecetate, cyclopentylpropionate andfi-chloropropionate.

By reduction of a Z-alkoxyrnethylene derivative ofdihydroallotestosterone, l9-nor-dihydroallotestosterone, or of one ofHer-substituted derivatives thereof, with a double metal hydride thereare obtained the respective S-hydroxy derivatives. it has beendiscovered that such fi-hydroxy enol-ether compounds are very unstablein acid medium and in the presence of a proton acceptor; under theseconditions they dehydrate with simultaneous transformation of theZ-allroxymethylene group into the respective aldehyde, thus giving riseto the formation of the Z-fQrrnyin -androstenes. By esterification withtie anhydrides or chlorides of carboxylic acids, by conventionalmethods,there are obtained the respective esters.

The method set forth above is illustrated by the following sequence ofreactions:

OH OH 1 R1 I R H B l 110-0: R o-o- O: HQ MN i I II 11 3,li?7,485Patented Feb. 12, 1963 .aikynyl group, was converted into thecorresponding ether, i.e., the 2-alkoxymethylene derivative (1), byreaction at room temperature and for a prolonged period of time,preferably for 15 to 24 hours, with a diazoallcane,

such as diazomethane or diazoethanc, or by refluxing with an alkyliodide, such a methyl or isopropyl iodide, in the presence of anhydrouspotassium carbonate and acetone.

By reduction of the 2-alkoxymethylene-androstan-17,6 ol-3-one or of oneof its 17ot-SllbSii'EUtEd derivatives (i: ,=methyl) with a double metalhydride, such as sodium borohydride, at room temperature and in anadequate solvent, such as methanol, for a short period of time,preferably between 15 minutes and 2 hours, there is obtained a mixtureof the 30: and BB-hydroxy compounds, the Sfl-isomer predominating in themixture, thus affording the 2-a1koxyrnethylene-androstane-3[3,17,6-diolsas Well as their l7-alkyl, alkenyl and alkynyl derivatives (H:R=rnethyl). Alternatively, this reduction may be conducted through theuse of tetrahydrofuran as solvent, for a prolonged period of time,between 36 and 48 hours.

When the product obtained in the above reduction is subjected to an acidtreatment, using for example hydrochloric acid or dilute sulfuric acidin the presence of a proton acceptor, such as acetone, which may also bethe solvent employed for the reaction, or which may be used in a smallamount when using another solvent such as ethyl acetate, at atemperature between 0 and 25 C., there is produced an immediatedehydration with the simultaneous transformation of the alkoxymethylenegroup, thus giving rise to the l-formyl-Nandrostenes, that is, to2-formyl-A -androsten--01, l-formyl-17u-alkyl-n -androsten-l7B-ol,2-formyl-l7et-alkenyl-A -and1'osten-175421 and 2-formyl-l7oc-alkinyl Aandrosten-l7/3-ol (III:

R=methyl) The same Z-fOrmyl-A -androsten derivatives may be alsoobtained by simply dissolving the ,3-hydroxy enolother (H) in aceticacid and keeping the solution at room temperature for a prolonged periodof time.

In the same manner, by reduction with sodium borohydride of aZ-aIkOXymethylene derivative of l9-nor-dihydroallotestosterone or of oneof the 17 tit-substituted derivatives thereof, there are obtained therespective 3-alcohols, which upon treatment with acid furnish thecorresponding 2-forrnyl-19-nor-A -androstenes.

For preparing the esters of the compounds heretofore set forth,Z-forrnyl-M-androsten-175-01 or its l9-noranalog are treated with anacid anhydride or chloride derived from a hydrocarbon carboxylic acid ofthe type described previously, in solution in pyridine and benzene, orsimply using pyridine as solvent, at room temperature enemas for severalhours, or heating under reflux or on the steam bath for 1 hour.

The esters of the l7a-substituted compounds are obtained by treatmentwith an acid anhydride or chloride in benzene solution and in thepresence of p-toluenesulfonic acid as catalyst.

The following examples serve to illustrate but are not intended to limitthe scope of the invention:

Example I A suspension of 5 g. of2-methoxymethylene-dihydroallotestosterone, obtained by etherificationof Z-hydroxymethylene-dihydroallotestosterone with diazornethane, in 75cc. of methanol was cooled to OS C. and treated dropwise under stirringwith a solution of 6 g. of sodium borohydride in 30 cc. of methanol. Thereaction mixture was stirred for 2 hours further at room temperature,the excess of reagent was then destroyed by the addition of a few dropsof glacial acetic acid and the mixture was poured into water; theprecipitate was collected by filtration, washed and dried.Crystallization from acetone yielded 2 methoxymethylene androstane3fl,17,8 diol, M.P. 158-160 C., [ab -35 (chloroform).

A stirred suspension of 2 g. of the above compound in 20 cc. of acetonewas treated at room temperature with 2 drops of concentratedhydrochloric acid; after 2 minutes the starting material had dissolvedand the aldehyde resulting from the reaction precipitated spontaneously;it was collected by filtration and recrystallized from ethyl acetate,thus affording Z-fOrmyl-A -androsten-175-01; M.P. 196-198" C., [aJ --107(chloroform), 7t max. 232, 309 mu, log e 4.08, 1.64.

In another experiment 1 g. of the steroid was dissolved in 20 cc. ofethyl acetate and treated with 1 drop of concentrated hydrochloric acidand 2 drops of acetone, thus affording also the 2-formyl-A-androsten-175-01, identical with the product obtained by the abovemethod.

Example II In accordance with the method described in Example I, 2 g. of2-methoxymethylene-17a-methyl dihydroallotestosterone was reduced withsodium borohydride to produceZ-methoxyrnethylene-17a-methyl-androstane-3B,17/3- diol, with M.P.146-149 C., [a] -53 (chloroform).

The above compound was dissolved in 20 cc. of acetone, cooled to C. andtreated with 1 drop of concentrated hydrochloric acid. The solution wasstirred for minutes at 0 C., slowly treated with water until completeprecipitation and the product was collected, thus giving2-formyl-17e-methyl-A -androsten-17 8-01; M.P. 138-140 C., [oc] +70(chloroform), A max. 232, 313 mu, log a 4.10, 1.59.

Example III A solution of 1.25 g. ofZ-methoxymethylene-lhmethyl-androstane-Bfi,17fi-diol in 50 cc. of aceticacid was kept standing for 10 hours at room temperature; the precipitateformed was collected, washed with water to neutral, dried under vacuumand recrystallized from acetone-water, thus furnishing 550 mg. of2-formyl-17amethyl-n -androsten-17 3-01, identical with the one obtainedin the preceding example.

Example IV To a solution of 5 g. of2-hydroxymethylene-17a-ethylandrostan-l7fi-ol-3-one in 100 cc. ofmethanol was added an ether solution of diazomethane prepared from 2 g.of nitrosomethylurea and the mixture was kept overnight at roomtemperature; a few drops of acetic acid were then added and the mixturewas concentrated until2-methoxymethylene-l7rx-ethyl-androstan-17;8--o1-3-one separated incrystalline form.

A solution of l g. of the above product in 50 cc. of tetrahydrofuran wastreated with a suspension of 1 g. of sodium borohydride in 10 cc. oftetrahydrofuran and the mixture was stirred for 48 hours at roomtemperature;

d the excess of reagent was then destroyed with 1 cc. of acetic acid,water was added until complete precepitation and the product wascollected by filtration, thus affording a mixture ofZ-methoxymethyIene-17ot-ethyl-androstane-3fl,17e-diol and its3tt-epimer, which was used for the next step without furtherpurification.

The above crude diol was treated with hydrochloric acid in acetone, byfollowing the method described in Example I, to produce2-formy1-17ot-ethyl-A -androsten- 17 8-01.

Example V The method of Example I was repeated, but using as startingcompounds 2-hydroxymethylene-19-nor-androstan-17fi-ol-3-one and2-hydroxymethylene-Not-methyl- 19-nor-androstan-l7fi-ol-3-one, thusobtaining as final products 2-formyl-19-nor-A -androsten-17 8-01 and2-formyl-lh-methyl-l9-nor-A -androsten-17 3-01.

Example VI A solution of 500 mg. of 2-formyl-A -androsten-175-01 in 2cc. of pyridine and 1 cc. of acetic anhydride was kept overnight at roomtemperature, then poured into water and the precipitate formed wascollected by filtration and dried under vacuum. Crystallization fromacetone-hexane afforded the acetate of Z-forrnyl-A -andr0sten-17fi-ol;

MP. l6l-163 C., [411 +84 (chloroform).

By the same method, but using 2-formyl-19-nor-A androsten-17/3-ol therewas obtained the corresponding acetate.

Example VII From a solution of 500 mg. of Z-formyl-A -androsten- 17,8-01in cc. of benzene there was distilled 25 cc. in order to remove moistureand then 0.27 cc. of pyridine and 0.75 cc. of undecenoyl chloride wereadded; the mixture was refluxed under anhydrous conditions for 1 hour,cooled and the solution was filtered through 15 g. of alumina, theneluting the column with 1 l. of benzene; the solvent was evaporated andthe residue chromatographed, thus furnishing the undecenoate ofZ-fOrmyI-A -androsten- 1713-01 as an amorphous solid; [041 +65(chloroform), A max. 232-, 311, log 6 4.11,1.69.

Example VIII By following the method described by H. J. Ringold et al.,.l.A.C.S., 81, 427 (1959), 5 g. of 17a-ethyny1-dihydroallotestosteronewas condensed with ethyl formate in benzene solution and in the presenceof sodium hydride, and the resulting 2-hydroxyrnethylene derivative wasconverted into the respective methyl ether by treatment withdiazomethane. By following the method described in Example I, the abovecompound was successively transformed intoZ-methoxymethylene-l7a-ethynyl-androstane- 3,17 8'diol and2-formyl-17a-ethynyl-A -androsten-l7fi-ol.

A mixture of l g. of the above compound, 50 cc. of benzene, 2 cc. ofacetic anhydride and 500 mg. of paratoluenesulfom'c acid was kept atroom temperature for 24 hours and then diluted with water; the benzenelayer was separated, consecutively washed with 5% aqueous sodiumcarbonate solution and water, dried over anhydrous sodium sulfate andevaporated to dryness under reduced pressure. By chromatography of theresidue followed by crystallization from acetone-hexane of the solidfractions there was obtained the acetate of 2- formyl-17a-ethynyl-A-androsten-17 3-01.

Example IX following the method described in the preceding example, thusgiving the caproate of 2-formy1-17a-vinyl-A -androstem-175ml.

Example X A solution of 1.5 g. ofZ-hydroxymethyleue-19-nordihydroallotestosterone in 50 cc. of methanolwas treated with an excess of an ether solution of diazoethane.

The resulting ethyl ether was allowed to react with 1.7 g. of sodiumborohydride in methanol solution, in accordance with the procedure ofExample 1, but stirring for only minutes at room temperature, thusobtaining Z-ethoxymethylene-l9-norandrostane-3,17B-diol. By reaction ofthis compound with hydrochloric acid in acetone, in accordance with themethod of Example I, there was finally obtained 2-formyl-19-nor-A-androsten-176-01, identical with the compound obtained in Example V.

By subsequent esterification with propionic anhydride in pyridine, inaccordance with the method of Example VI, there was produced thecorresponding propionate.

Example XI The method of Example VIII was repeated, but using asstarting compound 17a-ethynyl-l9-nor-dihydroallotestosterone, thusobtaining consecutively 2-hydroxymethylene 17aethynyl-l9-nor-dihydroallotestosterone, 2- rnethoxymethylene 17aethynyl-19-nor-dihydroailotestosterone,Z-methoxymethylene-17a-ethynyl-19-nor-androstane-3,17fl-diol, 2formyl-17u-ethynyl-19-nor-A -androsten-17,B-oi and2-formyl-17a-ethynyl-l9-nor A androsten-l7fi-o1 acetate.

Example XII By following the method of Example VI, but using propionicor valeric anhydride as esterifying agents, 2- formyl-n -androsten-173-01 was converted into the propionate of 2-formyl-A -andr0sten-175-01,M.P. 140-144 C., [(11 +74 (chloroform), A max. 2 32, 310 m log 6 4.13,1.64, and the valerate of 2-formyl-A -androsten-17/3- ol, [a] +69(chloroform), A max. 232, 308 mp, log e 4.03, 1.67.

Example XIII By following the esterification method of Example VIII2-formyl-17a-methy1-A -androsten-17;8-ol was treated with aceticanhydride in benzene solution and in the presence of p-toluenesulfonicacid, thus producing the acetate of 2-formyl-l7a-methyl-A-androsten-175-01.

In a similar manner, but using caproic and cyclopentylpropionicanhydrides as esterifying agents, there were obtained the caproate andcyclopentylpropionate of 2- formyl-17u-methyl-A -androsten-1713-01.

5 We claim:

1. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen and methyl;R is selected from the group consisting of hydrogen, a lower alkylgroup, a lower alkenyl group and a lower alkynyl group; and R isselected from the group consisting of hydrogen and a hydrocarboncarboxylic acyl group of less than 12 carbon atoms.

. 2-formyl-A -androsten-175-01.

. 2-forrnyl-17a-methylA -androsten-176-01.

. 2-formyl-17u-vinyl-A -androsten-1713-01.

. 2-formyl-17u-ethynyl-A -androsten-17,8-01.

. 2-formyl-19-nor-A -a-ndrosten-175-01.

. 2-formyl-l7a-methyl-l9-nor-A -androsten-175-01.

. 2-formyl-17a-ethynyl-19-nor-A -androsten-175-01.

The hydrocarbon carboxylic acid esters of less than 12 carbon atoms of2-formyl-A -androsten-17 8-01.

10. The acetate of Z-formyl-M-androsten-17,8-01.

11. The propionate of 2-formyl-A -androsten-17 3-01.

12. The valerate of Z-formyl-M-androsten-175-01.

13. The undecenoate of 2-forrnyl-A -androsten-17,6-01.

14. The acetate of 17a-methyl-2-formyl-A -androsten- 175-01.

15. A process for producing a 2-formyl-A androsten- 1713-01 comprisingreducing a 2-lower alkoxymethylene androsten-17;3-ol-3-one with a doublemetal hydride and treating the thus formed 2-loweralkoxymethyleneandrostan-3,l7 9diol with a mineral acid selected fromthe group consisting of hydrochloric acid and. sulfuric acid in thepresence of a proton acceptor and acetic acid.

No references cited.

1. A COMPOUND OF THE FOLLOWING FORMULA: